RETRACTED: NAD(P)H:quinone oxidoreductase 1 protects lungs from oxidant-induced emphysema in mice

Chronic obstructive pulmonary disease (COPD) is the fourth major cause of death in the United States and the only disease in the top ten causes of death with a rising incidence in the United States [1]. COPD is a slowly progressive disease characterized by airflow limitation, which is largely irreversible [2]. The development of pulmonary emphysema is a frequent observation in patients with COPD. The incidence of emphysema is reaching worldwide epidemic proportions and predicted to displace stroke as the third major worldwide cause of mortality by 2030. The pathologic feature of pulmonary emphysema is alveolar destruction with the loss of lung functional units. The development of emphysema is accompanied by accumulation of inflammatory cells such as macrophages and neutrophils in the airways and lung parenchyma. The molecular pathogenesis of emphysema includes both protease-antiprotease imbalance and oxidant stress [3–5]. Tobacco smoke is a dominant risk factor for the development of emphysema [6], which has been shown to induce oxidative stress and up-regulate genes responsible for protection from oxidant injury [7]. However, only 15–20% of smokers develop clinically recognized emphysema and approximately 25% of patients with emphysema are lifelong non-smokers [8]. These observations suggest both that host factors contribute to disease susceptibility and that additional environmental exposures are likely to contribute to disease pathogenesis [9]. There are currently no therapies available to slow the rate of decline of lung function in patients with emphysema. Understanding the fundamental mechanisms that contribute to disease pathogenesis could provide insight into novel therapeutic approaches to this common and devastating disease. The lungs are continuously exposed to environmental toxicants, which may lead to enhanced oxidant stress produced either by phagocytes or other cell types within the lung. Normally, the lungs can tolerate the stresses imposed by the ambient environment through the presence of well-developed antioxidant systems [10]. However, when the balance shifts in favor of oxidants, from either an excess of oxidants and/or depletion of its antioxidant responses, oxidative stress can occur. Previous studies have reported that markers of oxidative stress (8-isoprostanes) are elevated in the breath and serum of patients with COPD [11]. Numerous studies have demonstrated that the susceptibility of the lung to oxidative injury depends largely on the up-regulation of protective antioxidant systems [12]. An important transcriptional regulator of antioxidant pathways, Nuclear factor-erythroid factor 2 (Nrf2), has been demonstrated to be essential in cigarette smoke-induced emphysema in mice [13–14]. Nrf2-deficient mice have also shown exacerbated elastase-induced emphysema when compared with control mice [15]. These studies support the potential importance of oxidant stress in the pathobiology of pulmonary emphysema. Nrf2 has an essential protective role in the lungs against emphysema through the activation of antioxidant response elements (ARE) and induced transcription of potentially thousands of ARE-dependent genes. Studies demonstrate that Nrf2 exerts its protective effects through transcriptional activation of anti-proteases, as well as, antioxidants in alveolar macrophages [15]. Many studies have utilized downstream activity of AREs, such as NAD(P)H:quinone oxioreductase 1 (NQO1), as a readout for Nrf2 activity. However, the functional role of individual ARE-dependent genes in the pathogenesis of emphysema remains largely unexplored. NQO1 is a flavoprotein that catalyzes a two electron reduction of quinones, and requires NADH or NADPH as a cofactor. NQO1 may exert either anti-oxidant or pro-oxidant properties depending on the quinone substrate. NQO1 is highly induced by Nrf2 nuclear translocation and binding to AREs. In this setting, NQO1 may act as an antioxidant enzyme by regenerating antioxidant forms of ubiquinone and vitamin E quinone. The role of Nrf2 in human emphysema is supported, in part, by reduced levels of NQO1 in lung macrophages obtained from patients with emphysema [16] and the level of NQO1 from whole lung is inversely associated with severity of COPD [17]. These studies support that reduced Nrf2 activity is associated with emphysema, but do not address the functional role of NQO1 in disease progression. Based on the putative antioxidant potential of NQO1 and the association with reduced levels in human emphysema, we hypothesized that NQO1 is protective in the development of emphysema through attenuation of oxidant stress. In the present study, we demonstrate in vivo a critical protective role of NQO1 in oxidant-induced emphysematous lung disease utilizing mouse models. These novel observations highlight a direct functional role of NQO1 in the pathogenesis of emphysema and identify a potential novel therapeutic target for COPD.